A) Field of the Invention
The invention relates to phosphonated Rifamycins. These compounds are useful as antibiotics for prophylaxis and/or treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
B) Brief Description of the Prior Art
Osteomyelitis is an inflammation of bone caused by a variety of microorganisms, mainly Staphylococcus aureus (Carek et al., American Family Physician (2001), Vol 12, 12:2413-2420). This painful and debilitating disease occurs more commonly in children. Within the adult population, diabetics and kidney dialysis patients are also vulnerable. The acute form of the disease is treatable with antibiotics, but requires a lengthy period of daily therapy. It can, however, revert to a recurrent or chronic form requiring repeated hospital stays and heavy treatment regimens.
The Rifamycins are a class of semisynthetic antibacterial ansamycins, several members of which are currently used clinically or are under clinical evaluation (Burman et al, Clin. Pharmacokinet. (2001), 40:327-341). Rifamycins target the bacterial DNA-dependent RNA polymerase with 2-4 orders of magnitude greater affinity than for the equivalent eukaryotic enzymes (Floss and Yu, Chem. Rev. (2005), 105:621-632). Rifamycins act by binding a well defined site on the β subunit of the RNA polymerase holoenzyme, and as a result, interfere with and inhibit the initial phase of RNA synthesis. The common structural scaffold of these inhibitors presents a well defined position which allows for the modulation of their pharmacokinetic and pharmacodynamic properties without substantially altering their mode of binding. This has resulted in a number of well investigated compounds within the class, including Rifampicin (U.S. Pat. No. 3,342,810), Rifapentin (U.S. Pat. No. 4,002,752), Rifandin (U.S. Pat. No. 4,353,826), Rifabutin (U.S. Pat. No. 4,219,478), Rifalazil (U.S. Pat. No. 4,983,602) and Rifaximin (U.S. Pat. No. 4,341,785). Recently, a number of 25-deacetyl analogs have also been demonstrated to be attractive antibacterials (US patent application 2005/043298). Rifamycins are extremely potent against Gram positive pathogens, less so against the Gram negative ones, and display side effects generally only at high dose or in the presence of Cytochrome P3A inhibitors. Their unique ability to affect bacteria in a quiescent state, which may stem from their need for short bursts of RNA synthesis even in the absence of growth, makes them prime candidates for chronic infections, often in combination so as to avoid a relatively high frequency of resistance. In this respect, Rifampicin, generally in combination with other antibacterials, has resulted in attractive outcomes in the treatment of bone and joint infections (Darley and McGowan, J. Antimicrob. Chemother. (2004) 53, 928-935; Widmer et al, Clin. Infect. Dis. (1992) 14, 1251-1253)
Bisphosphonates are well-characterized bone-seeking agents. These compounds are recognized for having a high affinity to the bones due to their ability to bind the Ca2+ ions found in the hydroxyapatite forming the bone tissues (Hirabayashi and Fujisaki, Clin. Pharmacokinet. (2003) 42(15): 1319-1330). Therefore, many different types of bisphosphonate-conjugated compounds have been made for targeting drugs selectively to the bone, including proteins (Uludag et al., Biotechnol Prog. (2000) 16:1115-1118), vitamins (U.S. Pat. No. 6,214,812, US 2003/0129194 and WO 02/083150), tyrosine kinase inhibitors (WO 01/44258 and WO 01/44259), hormones (U.S. Pat. No. 5,183,815 and US 2004/0116673) and bone scanning agents (U.S. Pat. No. 4,810,486). These and other bisphosphonate derivatives have been used as therapeutic agents for bone diseases such as arthritis (U.S. Pat. No. 4,746,654), osteoporosis (U.S. Pat. Nos. 5,428,181 and 6,420,384), hypercalcemia (U.S. Pat. No. 4,973,576), and bone cancers (U.S. Pat. No. 6,548,042).
Several strategies have also been investigated for targeted delivery of antibiotics (U.S. Pat. No. 5,900,410, US 2002/0142994; US 2004/0033969, US 2005/026864). For bone-targeted delivery of antibiotics, some have suggested the use of bisphosphonated-antibiotics. However, only a few of such compounds have actually being synthesized, including tetracyclines, β-lactams and fluoroquinolones (U.S. Pat. Nos. 5,854,227; 5,880,111; DE 195 32 235; Pieper and Keppler, Phosphorus, Sulfur and Silicon (2001) 170:5-14; and Herczegh et al. J. Med. Chem. (2002) 45:2338-41). Furthermore, none of these compounds has been administered in vivo or shown to have any bone-targeting activity.
Despite the progress which has been made in the past years, bone-specific delivery is still limited by the unique anatomical features of the bones. Although bisphosphonate modification might be a promising method, there is no certainty of success because several decades of progress demonstrate that therapeutically optimized bisphosphonate derivatives have to be designed and optimized on a compound-to-compound basis (Hirabasashi and Fujisaki, Clin Pharmacokinet (2003), 42(15):1319-1330).
In view of the above, there is a need for better administrable drugs for the prevention and treatment of bone and joint infections. More particularly, there is a need for highly active phosphonated derivatives of Rifamycins capable of achieving both time-controlled (or sustained) and spatially controlled (or targeted) drug delivery to the bones.
The present invention fulfills these needs and also other needs as will be apparent to those skilled in the art upon reading the following specification.